1. Field
The present invention relates to pharmaceutical compositions. More particularly, the invention relates to a solid pharmaceutical composition comprising a) a solid pharmaceutically active compound which has a melting point xe2x89xa737xc2x0 C. and b) a fatty acid or a fatty acid salt or a mixture of a fatty acid and a fatty acid salt, characterized in that the constituents of a) and b) show a depression of their melting points to xe2x89xa637xc2x0 C. upon contact with an aqueous solution.
2. Description
Many pharmaceutically active compounds exhibit low solubilities and low dissolution rates in the biological environment. Examples include cyclosporine, nifedipine, ritonavir, griseofulvin, ubidecarenone, danazol, halofantrine, and tetrahydrolipstatin. Because of the low solubility and the low dissolution rate of the pharmaceutically active compounds, only a certain percentage of the drug molecules is dissolved from the crystals. Undissolved drug crystals exhibit no or very limited therapeutic activity in most cases, independent whether a systemic action (requires drug absorption) or a localized effect (within the lumen of the gastrointestinal tract) is desired. Due to the low dissolution of the active compound, higher doses have to be administrated which might result in an increased danger of side effects. Furthermore it has been found that the presence of food might effect the dissolution, absorption and activity of the compound to a large extend. As an example, the bioavailability of alpha-tocopherol-nicotinate increased 28-fold in the fed status compared to the fasted state [William N. Charman et al., J. Pharm. Sci: 86, 269-282 (1997)]. Other examples include danazol, halofantrine and etretinate. It is obvious for those skilled in the art that the high impact of food on the dissolution of the drug leads to an unpredictable performance of the drug. However, a low variation of the drug dissolution is a necessity to achieve the desired concentration for the pharmaceutically effect and to avoid the toxic effects due to overdosing. A pharmaceutically active compound can only be accepted if a reliable pharmacokinetic profile can be achieved.
The need of the development of drug delivery systems to overcome the high variation of drug dissolution has been widely recognized. Approaches include the development of solid dispersions (xe2x80x9csolid solutionxe2x80x9d) [A. T. M. Serajuddin, J. Pharm. Sci., 88, 1058-1066 (1999)]. The main disadvantage of this approach is the thermodynamic instability of the supersaturated solid dispersion, which might lead to crystallization processes leading to decreased dissolution velocities and unpredictable bioavailbilities.
Another approach to decrease the impact of food effects is the production of drug nanoparticules by wet-milling (U.S. Pat. Nos. 4,540,602 and 5,145,684) or High Pressure Homogenization (U.S. Pat. No. 5,858,410). However, disadvantages include the contamination of the product with abrasive material from the milling process. Furthermore, both processes require the presence of suspending liquids and the primary product is a nanosuspension and not dry nanoparticles. The prevention of the increase in particle size due to aggregation or Ostwald ripening is very challenging. Stabilization of the submicrometer sized particles often requires the time and cost intensive removal of the previously added suspension liquid by drying or cryodrying processes. Other disadvantages include the long processing time in wet milling (hours to several days) and the increase in temperature and the possible formation of radicals during the high pressure homogenization process [R. Lander et al., Biotechinol. Prog., 16, 80-15(2000)]. Changes of drug modifications have also to be considered as a result of the milling processes.
It must also be kept in mind, that amorphous drug molecules and drug nanoparticles might degrade faster than the unprocessed material due to the increased surface area. Other approaches include the administration of the solubilized pharmaceutically active compound. However, this approach might lead to problems related to the chemical stability of the active compound, because degradation processes will occur more rapidly in the solubilized state compared to the crystalline state.
For example, lipase inhibitor molecules orlistat (tetrahydrolipstatin), or structurally related compounds, e.g. 2-oxy-4H-3,1-benzoxanzin-4-ones as described in WO00/40569, or 2-oxo amide triacylglycerol analogues [S. Kotsovolou et al., J. Org. Chem., 66: 962-967 (2001)] are molecules that may degrade during storage by different mechanisms. It is well known that degradation velocity depends to a large extent from the physicochemical state of the active compound. In general, drug crystals have higher chemical stability compared to drug molecules in the amorphous or liquid state. Therefore, for good storage stability it is desirable to incorporate drug molecules in the crystalline form into the drug delivery system. It is, however, also well known, that in most cases pharmacoactivity is related to physicochemical states with high mobility, e.g. the solubilized or molten molecule. Therefore, from the point of pharmacoactivity, the drug molecule must be either given in a solubilized form or transform into a solubilized form within the body.
Both stability and activity aspects have to be considered. Therefore, the development of a drug-crystal loaded carrier which releases a solubilized drug is the most desirable case. This concept is easily realized for water-soluble drugs (e.g. ascorbic acid). However, the in situ transformation of poor water-soluble drugs remains a challenge.
The subject invention addresses this challenge.
The subject invention provides a solid pharmaceutical composition, which comprises a solid pharmaceutically active compound that has a melting point xe2x89xa737xc2x0 C., and a fatty acid or a fatty acid salt or a mixture of a fatty acid and a fatty acid salt. The pharmaceutically active compound and the fatty acid or a fatty acid salt or a mixture of a fatty acid and a fatty acid salt are present in amounts such that when the composition is contacted with an aqueous solution having a pH value xe2x89xa68, the melting point of the composition is less than the melting point of the solid pharmaceutically active compound and xe2x89xa637xc2x0 C.